Production method of optically active trans-vinylsulfide alcohol

ABSTRACT

A method for producing an optically active trans-vinylsulfide alcohol having the formula: ##STR1## wherein R 1  represents an alkyl group or an aryl group, comprising the step of reducing a trans-vinylsulfide ketone with a borane reducing agent in the presence of an optically active oxazaborolidine and an additive.

This is the national phase of PCI/JP96/03185, filed Oct. 30, 1996.

TECHNICAL FIELD

The present invention relates to a method for producing an opticallyactive trans-vinylsulfide alcohol useful as a synthetic material ofpenem or carbapenem compounds.

BACKGROUND ART

Various researches have heretofore made for penem or carbapenemcompounds, since they have wide and strong antimicrobial activities. Inthe production thereof, (1'R, 3R, 4R)-3-(1'-protectedhydroxyethyl)-4-acyloxy-2-azetidinone derivatives (i.e.,"acyloxyazetidinone derivatives" hereinbelow) are used as an excellentsynthetic intermediate and various synthetic methods are reported (seeN. Ueyama et al., JP-A-62-84057).

At present, as a production method of acyloxyazetidinone derivatives,the following method is known (see JP-A-3-127773). ##STR2## wherein ORrepresents a protected hydroxy group, X represents an alkyl or arylgroup, and Y represents an acyl group.

Thus, this method is a method capable of safe and efficiently producingthe desired acyloxyazetidinone derivatives (V) by reacting (1'R, 3S,4R)-3-(1'-protected hydroxyethyl)-4-substituted thio-2-azetidinonederivatives (IV) (i.e., "substituted thioazetidinone derivatives"hereinbelow) with a carboxylic acid in the presence of a coppercompound.

As explained above, although acyloxyazetidinone derivatives useful as asynthetic intermediate of penem or carbapenem compounds can be producedin an industrial scale from the substituted thioazetidinone derivativesas a starting material, there are various problems in the known methodsfor producing the starting substituted thioazetidinone derivatives.##STR3## wherein Hal represents a halogen atom, R¹ represents an alkylor aryl group, and OR and Y are the same as defined above.

According to the above-mentioned method (see JP-A-61-207373), anoptically active 1,3-butanediol (VI) is used as a starting material andthe substituted thioazetidinone derivatives (XI) can be obtained at ahigh yield from the cyclization reaction, with chlorosulfonyl isocyanate(CSI), of the intermediate trans-vinylsulfide (IX) obtained from thestarting material through the steps of the substitution at the1-position, the protection of the hydroxy group at the 3-position, thehalogenation and the dehydrohalogenation. This is an excellent method.However, according to the above method, there are still problems thatthe starting optically active 1,3-butanediol is expensive and also,since the multi-step synthesis is necessary for producing thetrans-vinylsulfide (IX), there are problems in the yield thereof.Furthermore, the cis-isomer (X), which is produced as a by-productduring the synthesis of the trans-vinylsulfide (IX) and which isextremely difficult to separate from the trans-isomer, affects theselectivity and yield of the subsequent cyclization reaction.

Furthermore, a method for obtaining an optically active1-substituted-3-hydroxybutane or optically active1-substituted-3-hydroxybutene from the optical resolution of the esterderivative of racemic 1-substituted-3-hydroxybutane or racemic1-substituted-3-hydroxybutene, respectively, with lipase (seeJP-A-4-228092 and JP-A-4-228093). This method is an effective method inview of the excellent selectivity, but the maximum yield of theoptically active substance is as high as 50%.

As mentioned above, there are various problems to be solved in theconventional production method for obtaining the substitutedthioazetidinone derivatives and there are strong need to solve theseproblems.

SUMMARY OF THE INVENTION

The objects of the present invention are to solve the above-mentionedproblems in the prior art and to provide a method for industriallyproducing an optically active trans-vinylsulfide alcohol, which isuseful as a synthetic material of penem or carbapenem compounds,effectively at a low cost under mild conditions.

In accordance with the present invention, there is provided a method forproducing an optically active trans-vinylsulfide alcohol having theformula (III): ##STR4## wherein R¹ represents an alkyl group or an arylgroup, comprising the step of reducing a trans-vinylsulfide ketonehaving the formula (I): ##STR5## wherein R¹ is the same as defined abovewith a borane reducing agent in the presence of an optically activeoxazaborolidine having the formula (II): ##STR6## wherein R² representsa hydrogen atom, an alkyl group, an aryl group or an aralkyl group andR³ and R⁴ are the same or different and represent an alkyl group, anaryl group or an aralkyl group and an additive for controlling thereduction of the olefin double bond of the trans-vinylsulfide ketone.

BEST MODE FOR CARRYING OUT THE INVENTION

The reaction according to the present invention is carried out by addinga borane reducing agent to a mixture of the trans-vinylsulfide ketone(I), optically active oxazaborolidine (II) and the additive.

In the present invention, R¹ in the starting trans-vinylsulfide ketone(I) has the same meaning of X in the substituted thioazetidinonederivative (IV) disclosed in the above-mentioned JP-A-3-127773.

Namely, R¹ is a leaving group, together with the adjacent sulfur atom inthe presence of a copper compound, and therefore, it is not specificallylimited unless the substitution reaction with the carboxylic acid in thepresence of the copper compound is inhibited. Nevertheless, in view ofthe easy availability and the cost, alkyl groups and aryl groups may beexemplified. The preferable examples of the alkyl groups are linear orbranched lower alkyl group having a carbon number of 1 to 6, preferably1 to 4, such as a methyl, ethyl, n-propyl, isopropyl, n-butyl,tert-butyl or hexyl group. The preferable examples of the aryl groupsare those having 6 to 10 carbon atoms, for example, a phenyl group;phenyl groups substituted, at the 3- or 4-position, with one or more ofhalogen atoms such as fluorine or chlorine atom, nitro groups, loweralkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,tert-butyl or hexyl groups or lower alkoxy groups such as methoxy orethoxy groups; a tolyl group; a xylyl group; naphthyl group.

Note that the term "lower" means herein a carbon atom number of,preferably 1 to 8, more preferably 1 to 4, unless otherwise specified.

The optically active oxazaborolidines (II) to be used in the presentinvention are known catalysts, as disclosed in, for example, E. J. Coreyet al., J. Am. Chem. Soc., 109, 7925-7926 (1987); E. J. Corey et al., J.Am. Chem. Soc., 109, 5551-5553 (1987); E. J. Corey et al., J. Org.Chem., 53, No. 12, 2861-2863 (1988); E. J. Corey et al., TetrahedronLett., 30, No. 46, 6275-6278 (1989); E. J. Corey et al., TetrahedronLett., 31, No. 5, 611-614 (1990); EP-A-305180; D. J. Mathre et al., J.Org. Chem., 56, No. 2, 751-762 (1991); S. Wallbaum et al.,Tetrahedron:Asymmetry, 3, No. 12, 1475-1504 (1992); JP-A-4-224556.

In the present invention, the preferable examples of R² are a hydrogenatom; a linear or branched lower alkyl group having 1 to 4 carbon atomssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl group;aryl groups having 6 to 10 carbon atoms such as a phenyl group, phenylgroups substituted, at the 3- or 4-position, with one or more of halogenatoms such as a fluorine or chlorine atom, lower alkyl groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or hexyl groups,a trifluoromethyl group or lower alkoxy groups such as methoxy or ethoxygroups, a tolyl group, a xylyl group, a 2-naphtyl group and aralkylgroups having 7 to 14 carbon atoms such as benzyl or phenetyl groups.The especially preferable substituents are methyl and phenyl groups.

The preferable examples of R³ and R⁴ are linear, branched or cyclicalkyl groups having 1 to 8 carbon atoms, more preferably 3 to 8 carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,hexyl, 2,2-dimethyl-1-propyl, cyclohexyl, cyclopentylmethyl or1,1,3,3-tetramethyl-1-butyl groups; aryl groups having 6 to 10 carbonatoms such as a phenyl group, phenyl groups substituted with, at the 3-or 4-position, one or more of halogen atoms such as a fluorine orchlorine atom, lower alkyl groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl or hexyl groups, a trifluoromethyl group,or lower alkoxy groups such as methoxy or ethoxy groups, a tolyl group,a xylyl group, a 2-naphtyl group; and aralkyl groups having 7 to 14carbon atoms such as benzyl or phenethyl groups. The especiallypreferable groups are alkyl groups having 3 to 8 carbon atoms and aphenyl group. Furthermore, the compounds having the same group for R³and R⁴ are preferable due to their easy synthesis. The phenyl group isespecially preferable. Typical examples of the optically activeoxazaborolidines (II) are(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol, (S)-1,3,3-triphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol.

Furthermore, the optically active oxazaborolidines (II) can be easilyproduced from easily available proline by a known method (see D. J.Mathre et al., J. Org. Chem., 56, No. 2, 751-762 (1991); EP-A-0305180;JP-A-4-224556; JP-A-6-41012). For example, ##STR7##

When optically active α,α-diphenyl-2-pyrrolidine methanol obtained fromoptically active proline by a known method is reacted with borane, thecompound having a hydrogen atom for R², and phenyl groups for R³ and R⁴can be obtained. Similarly, when reacted with trimethylboroxine, thecompound having a methyl group for R² can be obtained and, when reactedwith phenylboric acid, the compound having a phenyl group for R² can beobtained. Note that the commercially available optically activeα,α-diphenyl-2-pyrrolidine methanol can also be used.

The optically active oxazaborolidine (II) is used in an amount of notmore than stoichiometrical amount but sufficient amount to convert thereactants to the desired product. The amount is determined taking intoconsideration the prevention or suppression of the generation of thereduction with the noncatalytic reaction, i.e., the non-selectivereduction. The preferable amount is 0.05 to 0.1 equivalent amount to thetrans-vinylsulfide ketone (I).

As examples of the borane reducing agent to be used as the reducingagent, catechol borane (CB), borane dimethylsulfide complex (BMS),borane tetrahydrofuran complex (BTHF), can be exemplified. Among these,BMS is especially preferable. The amount of the reducing agent used isdetermined taking into consideration the prevention or suppression ofthe generation of the reduction with the noncatalytic reaction, i.e.,the nonselective reduction, preferably 0.34 to 1.0 equivalent amount tothe trans-vinylsulfide ketone (I).

The additives according to the present invention are defined as thereagent capable of controlling the reduction of the olefin double bondin the starting trans-vinylsulfide ketone (I) in the production methodof the present invention. By the use of this additive, the reactionproceeds efficiently under the mild conditions. Namely, when thereaction is carried out by adding the borane reducing agent to a mixtureof the trans-vinylsulfide ketone (I) and the optically activeoxazaborolidine (II), the following two types of the compounds (XII) and(XIII) obtained by the reduction of the olefin double bond areby-produced. This is believed that the olefin double bond near thesulfur atom, which coordinate to borane reducing agent, of the compound(I) is directly attacked by the hydride ion. Furthermore, a large amountof the cis-isomer (XIV) of the desired trans-product is produced as aby-product. ##STR8##

Accordingly, the additives according to the present invention are thosecapable of preventing the coordination of borane to the sulfur atom ofthe compound (I) and of possessing a coordination power such that thereducing capability of borane is not inhibited. The preferable additivesand the amounts to be used can be appropriately selected depending uponthe compound (I), the oxazaborolidine (II) and the borane reducingagent. The preferable examples of the additives are sulfide compoundsetc. The typical examples are dimethylsulfide, methylphenylsulfide,diphenylsulfide, di-n-butylsulfide, di-sec-butylsulfide,di-tert-butylsulfide, dibenzylsulfide. The preferable amount used is 0.5to 5.0 equivalent amount to the trans-vinylsulfide ketone (I).

The reaction can be carried out in an appropriate inert solvent. Theinert solvents mean those which can sufficiently dissolve the reactants,the desired product, the optically active oxazaborolidine and theadditives and which are not provide an interaction to the intendedreaction. Examples of the preferable solvents are aprotic non-basicsolvent, for example, ethers such as tetrahydrofuran, tetrahydropyran,dimethyl ether, diethyl ether, 1,2-dimethoxyethane, dioxane; acyclic orcyclic saturated hydrocarbons such as n-hexane, cyclohexane; aromatichydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbonssuch as dichloromethane. The especially preferable examples arenon-polar solvents such as toluene, n-hexane, cyclohexane, xylene.

The reaction is carried out in a manner such that the catalytic reactionrate is controlled by adding the borane reducing agent in theabove-mentioned nonpolar solvent to a mixture of the trans-vinylsulfideketone (I), the optically active oxazaborolidine (II) and the additivein the above solvent at a temperature of -10° C. to a room temperatureusually for 30 minutes to 2 hours. Then, the reaction is terminated byadding a reaction terminator such as aqueous saturated ammonium chloridesolution.

Note that, during the reaction, it is desirable to prevent thesuppression of the inactivation of the borane reducing agent and thedeactivation of the catalyst and to decrease the water content in thereaction system to suppress the decrease in the optical yield as much aspossible. Namely, in the preferable embodiment of the reaction accordingto the present invention, the reaction is carried out in a dehydratedcondition, for example, in the presence of a desiccant. Examples of thepreferable dehydrating agent are molecular sieve 4A (MS4A available fromNacalai Tesque Inc.), molecular sieve 3A (MS3A), molecular sieve 5A(MS5A), and inorganic compounds such as magnesium sulfate, sodiumsulfate, potassium carbonate.

The reaction is carried out in an inert gas atmosphere such as nitrogengas or argon gas.

After the completion of the reaction, the optically activetrans-vinylsulfide alcohol (III) can be used, as the concentrated crudeextract for the subsequent step by washing and drying the reactionmixture in a conventional manner, followed by evaporating off thesolvent. If necessary, the product can be purified by recrystallizationor chromatography such as liquid chromatography.

The optically active trans-vinylsulfide alcohol (III) obtained aboveare, after protecting the hydroxy group at the 3-position, converted tothe substituted thioazetidinone derivative (XI) by the cyclizationreaction with chlorosulfonyl isocyanate (CSI).

The protective group of the hydroxy group is not specifically limitedand any conventionally used protective groups may be appropriatelyselected. Examples of the preferable protective group aretri-substituted silyl groups such as trialkylsilyl group, aryl (alkyl)alkoxysilyl group, alkoxydiarylsilyl group, triarylsilyl group,alkyldiarylsilyl group, aryldialkylsilyl group, triaralkylsilyl group.More specifically, trimethylsilyl group, triethylsilyl group,triisopropylsilyl group, dimethylhexylsilyl group,tert-butyldimethylsilyl group, methyldiisopropylsilyl group,isopropyldimethylsilyl group, tert-butylmethoxyphenylsilyl group,tert-butoxydiphenylsilyl group, triphenylsilyl group,tert-butyldiphenylsilyl group, dimethylcumylphenylsilyl group,tribenzylsilyl group can be exemplified. The especially preferableprotective group is tert-buthyldimethylsilyl group. The protectingmethod is varied depending upon the nature or property of the protectivegroup. For example, when the hydroxy group is protected with atert-butyldimethylsilyl group, the protecting reaction can be carriedout by reacting 1 to 2 equivalent amount, based upon the hydroxy group,of tert-butyldimethylchlorosilane in the presence of a catalyst such asa tertiary amine (e.g., triethylamine), 4-dimethylaminopyridineaccording to a known method (see Tetrahedron Lett., No. 2, 99-102(1979)). In this reaction, amides such as N,N-dimethylformamide, ketonessuch as acetone, methylethyl ketone, ethers such as tetrahydrofuran,diethyl ether, aromatic hydrocarbons such as benzene, toluene, xylene,or any mixture thereof, may be preferably used as a solvent. After thecompletion of the reaction, the reaction mixture is diluted with anorganic solvent immiscible with water and then washed with an aqueoussaturated potassium hydrogen sulfate solution, water, an aqueoussaturated sodium hydrogen carbonate solution, and saturated brine, inthis order, followed by evaporating off the solvent. Thus, thetrans-vinylsulfide (IX) having the protected hydroxy group at the3-position.

The trans-vinylsulfide ketones (I) usable as the starting material inthe present invention may be easily produced by various known methods,but the following two methods are exemplified as the excellent methodfor efficiently obtaining the trans compounds suitable for use in thereaction of the present invention at a low cost under mild conditions.

First method: ##STR9##

Namely, according to this method, acetyl chloride is reacted withacetylene in the presence of aluminum chloride to prepare thechlorovinyl ketone. The resultant chlorovinyl ketone is condensated withmercaptan to obtain the desired trans-vinylsulfide ketone (I).

Second method: ##STR10##

This method can refer to R. K. Haynes et al., Aust. J. Chem., 41,881-895 (1988).

EXAMPLES

The present invention will now be further illustrated by, but is by nomeans limited to, the following Examples.

The NMR spectra of the compounds obtained in the following PreparationExamples and Examples were measured by ALPHA-500 (manufactured by JEOL,Japan). The solvent used was deuterio chloroform and tetramethylsilanewas used as an internal standard. The melting point (mp) was determinedby micro melting point apparatus (manufactured by Yanagimote Seisakusho,Japan).

As the column chromatography, silica gel (Kiesel gel 60 (Art. 7734)available from Merck Co.) was used.

The reaction solvent was dried by molecular sieve (i.e., pellet form(1/16) available from Nacalai Tesque Inc.), and the reducing agent wasused by diluting the commercially available product (available fromAldrich Co.) with dry toluene, followed by quantitative determination.

The conditions of high performance liquid chromatography (HPLC) usedwere as follows.

Column: Chiralcel OD 4.6×250 mm (manufactured by Daicel ChemicalIndustries Ltd.)

Column temperature: Room temperature

Detection wavelength: 254 nm

Eluent: n-hexane:isopropyl alcohol=95:5,

provided that n-hexane:ethanol=98:2 in

Example 8 and n-hexane:isopropyl

alcohol=99.75:0.25 in Example 9.

Column speed: 0.6 ml/min, provided that 0.5 ml/min was used in Example 8and 0.4 ml/min was used in Example 9.

Termination time: 40 minutes, provided that 80 minutes were used inExample 8 and 120 minutes were used in Example 9.

Preparation Example 1 Preparation of(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c]1,3,2 oxazaborol

Under argon stream, to a solution of (S)-α,α-diphenyl-2-pyrrolidinemethanol (3 g, 11.8 mmol) in dry toluene (90 ml) was added trimethylboroxine (1.13 ml, 8.0 mmol), followed by stirring for 1.5 hours. Afterthe argon stream was stopped and the toluene (22.5 ml) was recoveredunder normal pressures on an oil bath at 140° C., dry toluene (22.5 ml)was added. Furthermore, after this recovery operation was repeatedtwice, the resultant product was concentrated under normal pressures,and subsequently under a reduced pressure, to thereby obtain the titledcompound as a colorless crystalline.

Yield: 3.28 g (yield 100%);

NMR(δ ppm): 0.36 (3H, s, methyl at 1-position), 0.77-0.86 (1H, m, 1proton of methylene at 4-position), 1.55-1.79 (3H, m, 1 proton ofmethylene at 4-position, methylene at 5-position), 3.02-3.07 (1H, m, 1proton of methylene at 6-position), 3.32-3.37 (1H, m, 1 proton ofmethylene at 6-position), 4.35 (1H, dd, methine at 3a-position),7.13-7.62 (10H, m, ArH)

Preparation Example 2 Preparation of (E)-4-phenylthio-3-buten-2-one

To a solution of (E)-4-methoxy-3-buten-2-one (purity 90%, 5.66 ml, 49.9mmol) and thiophenol (5.13 ml, 49.9 mmol) in benzene (60 ml) was addedp-toluene 25 sulfonic acid-monohydrate (30 mg, 0.16 mmol), followed byheating while stirring on an oil bath at 55° C. for 30 minutes. Afterice cooling, an aqueous saturated sodium hydrogen carbonate solution wasadded thereto, followed by extracting with cyclohexane 3 times. Theorganic layer was washed with an aqueous saturated sodium hydrogencarbonate solution twice and with saturated brine, followed by dryingwith anhydrous magnesium sulfate. After concentrating under a reducedpressure, the residue was treated with the column chromatography (190 g,n-hexane:ethyl acetate=10:1). After evaporated under a reduced pressure,the titled compound was recrystallized from n-hexane-n-nonane to obtainas a colorless crystalline.

Yield: 3.04 g (yield 34.1%);

mp: 37.5-38.5° C.;

NMR(δ ppm): 2.20 (3H, s, methyl at 1-position), 6.02 (1H, d, olefin at3-position), 7.39-7.49 (5H, m, ArH), 7.70 (1H, d, olefin at 4-position)

Preparation Example 3 Preparation of(E)-4-(2-naphthylthio)-3-buten-2-one

To a solution of (E)-4-methoxy-3-buten-2-one (purity: 90%, 15.0 ml, 0.13mol) and 2-naphthalenethiol (21.16 g, 0.13 mol) in benzene (180 ml) wasadded p-toluene sulfonic acid-monohydrate (75 mg, 0.4 mmol), followed byheating, while stirring, on an oil bath at 50° C. for 70 minutes. Afterice cooling, an aqueous saturated sodium hydrogen carbonate solution wasadded thereto, followed by extracting with ethyl acetate four times. Theethyl acetate layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine twice and then dried withanhydrous magnesium sulfate. After concentrating under a reducedpressure, the residue was treated with the column chromatography (670 g,n-hexane:methylene chloride:ethyl acetate=1:0:0-1:3:0-2:0:1), followedby recrystallizing from n-hexane-ethyl ether to thereby obtain thetitled compound as a light brown crystalline.

Yield: 5.04 g (yield 16.7%);

mp: 62-64° C.;

NMR(δ ppm): 2.19 (3H, s, methyl at 1-position), 6.03 (1H, d, olefin at3-position), 7.78 (1H, d, olefin at 4-position), 7.50-7.57, 7.82-8.00(7H, m, ArH)

Preparation Example 4 Preparation of(E)-4-(tert-butylthio)-3-buten-2-one

To a solution of (E)-4-methoxy-3-buten-2-one (purity: 90%, 7.92 ml, 69.9mmol) and tert-butylmercaptan (5.54 ml, 48.9 mmol) in carbontetrachloride (70 ml) was added, under ice cooling, trifluoroacetic acid(7.54 ml, 97.9 mmol), followed by heating, under reflux, on an oil bathat 95° C. for 4 hours. After ice cooling, ethyl ether was added 5thereto, followed by washing with water (twice), an aqueous saturatedsodium hydrogen carbonate solution, water and saturated brine. Afterdrying with anhydrous magnesium sulfate, the resultant product wasconcentrated under a reduced pressure and the residue was treated withthe column chromatography (420 g, n-hexane:ethyl acetate=1:0-6:1) tothereby obtain the titled compound in the form of a pale yellow oil.

Yield: 6.93 g (yield 89.6%);

NMR(δ ppm): 1.44 (9H, s, (CH₃)₃ C), 2.21 (3H, s, methyl at 1-position),6.31 (1H, d, olefin at 3-position), 7.81 (1H, d, olefin at 4-position)

Example 1 Preparation of (R,E)-4-phenylthio-3-buten-2-ol

(E)-4-phenylthio-3-buten-2-one (178 mg, 1.0 mmol),(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c] [1,3,2]oxazaborol (28 mg, 0.1 mmol) and MS4A (Nacalai Tesque Inc., 500 mg) weredried by a vacuum pump, followed by substituting with an argon gas. Drytoluene (5 ml) and dimethylsulfide (3.0 mmol) were added thereto and,after ice cooling, a solution of borane dimethylsulfide complex intoluene (1.07M, 0.65 ml, 0.7 mmol) was dropwise added. After stirringfor two hours, an aqueous saturated ammonium chloride solution wasadded, followed by filtering through a cotton plug. The filtrate waswashed with ethyl acetate and, after separating an aqueous layer, theorganic layer was washed with 2NHCl, water, an aqueous saturated sodiumhydrogen carbonate solution, water and saturated brine. After dryingwith anhydrous magnesium sulfate, the extract containing the titledcompound as a main component was obtained by concentrating under areduced pressure. The NMR chemical shifts of the titled compound are asfollows.

NMR(δ ppm): 1.31 (3H, d, methyl at 1-position), 1.51 (1H, brs, OH), 4.40(1H, m, methine at 2-position), 5.89 (1H, dd, olefin at 3-position),6.42 (1H, d, olefin at 4-position), 7.23-7.38 (5H, m, ArH)

Further, the extract obtained by the concentration under a reducedpressure was analyzed by HPLC to obtain the yields of the desiredcompound and the by-products. The results are shown in Table I.Furthermore, as Comparative Example, the extract obtained by the similarmethod as mentioned above, except that the dimethylsulfide as theadditive was not used, was analyzed in the same manner. The results areshown in Table I.

                  TABLE I                                                         ______________________________________                                                   Yield (%)                                                          Compound No. (III) (ee)                                                                             (XII)    (XIII)                                                                             (XIV)                                     ______________________________________                                        Example 1    70 (90)  9        10   4                                           Comparative Example 59 (89) 16 13 12                                        ______________________________________                                    

Examples 2-4 Preparation of (R,E)-4-phenylthio-3-buten-2-ol

The results shown in Table II were obtained in the same manner as inExample 1, except that, instead of the dimethylsulfide as the additive,methylphenylsulfide (Example 2), diphenylsulfide (Example 3) anddi-tert-butylsulfide (Example 4) were used, respectively.

                  TABLE II                                                        ______________________________________                                                      Yield (%)                                                       Compound No.    (III) (ee)                                                                             (XIV)                                                ______________________________________                                        Example 2       67 (88)  2                                                      Example 3      65 (89)     2                                                  Example 4      61 (89)     8                                                ______________________________________                                    

Examples 5-7 Preparation of (R,E)-4-phenylthio-3-buten-2-ol

The results shown in Table III were obtained in the same manner as inExample 1, except that cyclohexane (Example 5), n-hexane (Example 6) andxylene (Example 7) were used, respectively, as a solvent, instead of thetoluene.

                  TABLE III                                                       ______________________________________                                                     Yield (%)                                                        Compound No.   (III) (ee)                                                     ______________________________________                                        Example 5      71 (89)                                                          Example 6       73 (87)                                                       Example 7       65 (89)                                                     ______________________________________                                    

Example 8 Preparation of (R,E)-4-(2-naphtylthio)-3-buten-2-ol

(E)-4-(2-naphthylthio)-3-buten-2-one (228 mg, 1.0 mmol),(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol (28 mg, 0.1 mmol) and MS4A (500 mg) were dried by a vacuumpump, followed by substituting with an argon gas. Dry toluene (5 ml) anddimethylsulfide (0.22 ml, 3.0 mmol) were added thereto and, after icecooling, a solution of borane dimethylsulfide complex in toluene (1.07M,0.65 ml, 0.7 mmol) was dropwise added. After stirring for two hours, anaqueous saturated ammonium chloride solution was added, followed byfiltering through a cotton plug.

The filtrate was washed with ethyl acetate and, after separating anaqueous layer, the ethyl acetate layer was washed with 2NHCl, water, anaqueous saturated sodium hydrogen carbonate solution, water andsaturated brine. After drying with anhydrous magnesium sulfate, theextract containing the titled compound as a main component was obtainedby concentrating under a reduced pressure. The NMR chemical shifts ofthe titled compound are as follows. Further, the HPLC analytical resultsare shown in Table IV.

NMR(δ ppm): 1.33 (3H, d, methyl at 1-position), 1.53 (1H, d, OH), 4.44(1H, m, methine at 2-position), 5.94 (1H, dd, olefin at 3-position),6.52 (1H, d, olefin at 4-position), 7.43-7.51, 7.77-7.82 (7H, m, ArH)

                  TABLE IV                                                        ______________________________________                                                      Yield (%)                                                       Compound No.    (III) (ee)                                                                             (XIV)                                                ______________________________________                                        Example 8       72 (93)  2                                                    ______________________________________                                    

Example 9 Preparation of (R,E)-4-(tert-butylthio)-3-buten-2-ol

(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c] [1,3,2]oxazaborol (28 mg, 0.1 mmol) and MS4A (Nacalai Tesque Inc., 500 mg) weredried by a vacuum pump, followed by substituting with an argon gas. Tothis mixture, (E)-4-(tert-butylthio)-3-buten-2-one (158 mg, 1.0 mmol)and dimethylsulfide (0.22 ml, 3.0 mmol) were added, which were thenwashed into the mixture with dry toluene (5 ml). After ice cooling, asolution of borane dimethylsulfide complex in toluene (1.07M, 0.65 ml,0.7 mmol) was dropwise added. After stirring for two hours, an aqueoussaturated ammonium chloride solution was added, followed by filteringthrough a cotton plug. The filtrate was washed with ethyl acetate and,after separating an aqueous layer, the ethyl acetate layer was washedwith 2NHCl, water, an aqueous saturated sodium hydrogen carbonatesolution, water and saturated brine. After drying with anhydrousmagnesium sulfate, the extract containing the titled compound as a maincomponent was obtained by concentrating under a reduced pressure. TheNMR chemical shifts of the titled compound are as follows. Further, theHPLC analytical results are shown in Table V.

NMR(δ ppm): 1.29 (3H, d, methyl at 1-position), 1.35 (9H, s, (CH₃)₃ C),1.46 (1H, d, OH), 4.36 (1H, m, methine at 2-position), 5.87 (1H, dd,olefin at 3-position), 6.36 (1H, d, olefin at 4-position)

                  TABLE V                                                         ______________________________________                                                      Yield (%)                                                       Compound No.    (III) (ee)                                                                             (XIV)                                                ______________________________________                                        Example 9       64 (88)  8                                                    ______________________________________                                    

INDUSTRIAL APPLICABILITY

According to the present invention, since the production of theoptically active trans-vinylsulfide alcohol useful as the syntheticmaterial of penem or carbapenem compounds, can be efficiently carriedout under a mild condition with a simplified steps and the improvementin the yield can be realized due to the fact that the present inventionis not an optical resolution method of a racemic mixture, and therefore,the present invention is industrially advantageous. Furthermore, thecompounds obtained at a high yield and a high selectivity according tothe present invention have a trans-isomer structure and provideexcellent yield and selectivity in the subsequent step and, as a result,the improvement can be obtained in the synthesis of penem or carbapenemcompounds.

We claim:
 1. A method for producing an optically activetrans-vinylsulfide alcohol having the formula (III): ##STR11## whereinR¹ represents an alkyl group or an aryl group, comprising the step ofreducing a trans-vinylsulfide ketone having the formula (I): ##STR12##wherein R¹ is the same as defined above with a borane reducing agent inthe presence of an optically active oxazaborolidine having the formula(II): ##STR13## wherein R² represents a hydrogen atom, an alkyl group,an aryl group or an aralkyl group and R³ and R⁴ are the same ordifferent and represent an alkyl group, an aryl group or an aralkylgroup in the presence of at least one sulfide compound selected from thegroup consisting of dimethylsulfide, methylphenylsulfide,diphenylsulfide, di-n-butylsulfide, di-sec-butylsulfide,di-tert-butylsulfide and dibenzylsulfide as an additive for controllingthe reduction of the olefin double bond of the trans-vinylsulfideketone, wherein said additive prevents coordination of the boranereducing agent to the sulfur atom of the trans-vinylsulfide ketone (I).2. A method as claimed in claim 1, wherein R¹ is a phenyl group or aphenyl group substituted with one or more of halogen atoms, nitrogroups, lower alkyl groups or lower alkoxy groups.
 3. A method asclaimed in claim 1, wherein R¹ is a phenyl group.
 4. A production methodas claimed in claim 1, wherein R² is a hydrogen atom, a lower alkylgroup, a phenyl group, or a phenyl group substituted with one or more ofhalogen atoms, lower alkyl groups, trifluoromethyl groups or loweralkoxy groups.
 5. A method as claimed in claim 1, wherein R² is a methylgroup or a phenyl group.
 6. A method as claimed in claim 1, wherein R³and R⁴ are the same alkyl groups, aryl groups or aralkyl groups.
 7. Amethod as claimed in claim 1, wherein R³ and R⁴ are 2-naphthyl groups,phenyl groups, phenyl groups substituted with one or more of halogenatoms, lower alkyl groups, trifluoromethyl groups or lower alkoxygroups.
 8. A method as claimed in claim 1, wherein R³ and R⁴ are phenylgroups.
 9. A method as claimed in claim 1, wherein the borane reducingagent is a borane dimethylsulfide complex.
 10. A method as claimed inclaim 2, wherein R² is a hydrogen atom, a lower alkyl group, a phenylgroup, or a phenyl group substituted with one or more of halogen atoms,lower alkyl groups, trifluoromethyl groups or lower alkoxy groups.
 11. Amethod as claimed in claim 3, wherein R³ is a methyl group or a phenylgroup.
 12. A method as claimed in claim 10, wherein R³ and R⁴ are thesame alkyl groups, aryl groups or aralkyl groups.
 13. A method asclaimed in claim 12, wherein R³ and R⁴ are 2-naphthyl groups, phenylgroups, phenyl groups substituted with one or more of halogen atoms,lower alkyl groups, trifluoromethyl groups or lower alkoxy groups.
 14. Amethod as claimed in claim 14, wherein R³ and R⁴ are phenyl groups. 15.A method as claimed in claim 12, wherein R³ and R⁴ are phenyl groups.16. A method as claimed in claim 13, wherein the borane reducing agentis a borane dimethylsulfide complex.
 17. A method as claimed in claim15, wherein the borane reducing agent is a borane dimethylsulfidecomplex.